Somatostatin, or somatotropin-release inhibitory factor (SRIF), is a cyclic peptide found in humans. It is produced widely in the human body and acts both systemically and locally to inhibit the secretion of various hormones, growth factors and neurotransmitters. The effects of somatostatin are mediated by a family of G protein-coupled receptors, of which five subtypes are known. These subtypes are divided into two subfamilies, the first comprising SSTR2, SSTR3 and SSTR5 and the second SSTR1 and SSTR4.
Somatostatin is involved in the regulation of processes such as for example cellular proliferation, glucose homeostasis, inflammation and pain.
In this aspect somatostatin or other members of the somatostatin peptide family are believed to inhibit nociceptive and inflammatory processes via the SSTR4 pathway.
A number of further therapeutic areas for SSTR4 agonists have been discussed (see e.g. Crider, A; Mini Rev. Med. Chem. 2002, 7, 213 (and references therein); WO 2010/059922 (and references therein).
Selective SSTR4 agonists have been disclosed, for instance, in J. Am. Chem. Soc. 1998, 120, 1368-1373.
WO 2010/059922 provides pyrrolidine carboxamide agonists of SSTR4.
U.S. Ser. No. 14/275,879 relates to 3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid amide derivatives as SSTR4 agonists.
However, there is further need for selective SSTR4 agonists, especially for non-peptidic agonists, which show high stability, permeability and other advantageous properties, such as oral efficacy and metabolic stability.